The retinal toxicity profile towards assemblies of Amyloid-? indicate the predominant pathophysiological activity of oligomeric species.

ABSTRACT: Amyloid-? (A?), reported as a significant constituent of drusen, was implicated in the pathophysiology of age-related macular degeneration (AMD), yet the identity of the major pathogenic A? species in the retina has remained hitherto unclear. Here, we examined the in-vivo retinal impact of distinct supramolecular assemblies of A?. Fibrillar (A?40, A?42) and oligomeric (A?42) preparations showed clear biophysical hallmarks of amyloid assemblies. Measures of retinal structure and function were studied longitudinally following intravitreal administration of the various A? assemblies in rats. Electroretinography (ERG) delineated differential retinal neurotoxicity of A? species. Oligomeric A?42 inflicted the major toxic effect, exerting diminished ERG responses through 30 days post injection. A lesser degree of retinal dysfunction was noted following treatment with fibrillar A?42, whereas no retinal compromise was recorded in response to A?40 fibrils. The toxic effect of A?42 architectures was further reflected by retinal glial response. Fluorescence labelling of A?42 species was used to detect their accumulation into the retinal tissue. These results provide conceptual evidence of the differential toxicity of particular A? species in-vivo, and promote the mechanistic understanding of their retinal pathogenicity. Stratifying the impact of pathological A? aggregation in the retina may merit further investigation to decipher the pathophysiological relevance of processes of molecular self-assembly in retinal disorders.

SUBMITTER: Naaman E 

PROVIDER: S-EPMC7708452 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature